The present application is being examined under the pre-AIA first to invent provisions.
This office action is in response to Applicants’ amendments/remarks received September 9, 2025.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 4-9, 16, 21, 24, 28 are canceled. Claims 1-3, 10-15, 17-20, 22-23, 25-27, 29-30 are under consideration.
Priority: This application is a CON of U.S. Application 16320137, filed January 24, 2019, now U.S. Patent 11708570, which is a 371 of PCT/US17/44104, filed July 27, 2017, which claims benefit of provisional application 62/367321, filed July 27, 2016.
Objections and Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 10-15, 17-20, 22-23, 25-27, 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Madison et al. (US 20160201047; IDS 03.01.23, previously cited). Madison et al. disclose modified Factor IX (FIX) polypeptides having improved procoagulant therapeutic properties, including increased activity and increased half-life (at least paragraphs 0007). Madison et al. disclose the modified FIX polypeptides contain one or more amino acid replacement(s) selected from positions including F342, T343, or E410 (at least paragraph 0008). Madison et al. disclose the modified FIX polypeptides comprise the FIX light chain and the FIX heavy chain, and further discloses the SEQ ID NOS. comprising the light chain and the heavy chains (at least paragraphs 0121-0122). Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419). While Madison et al. disclose the substitution at position E410 among other amino acid substitutions, it is expressly disclosed in Madison et al. that some of the variants displayed markedly increased catalytic activity compared to wild-type FIXa, including single amino acid substitutions FIXa-R338E, FIXa-R338A, FIXa-T343R, FIXa-E410N, and combinations thereof, such as at least R338E with E410N (paragraph 0602). It is disclosed that single amino acid substitutions at position E410 have an increased catalytic activity including 297% for E410N (p. 83 Table 14), 269% E410Q, 246% E410S, 248% E410A, 134% E410D (p. 85 Table 14). It is disclosed that single amino acid substitutions at positions R338 also have markedly increased catalytic activity, 361% R338A and 408% R338E (p. 84 Table 14), and further that the double amino acid substitutions at R338E/E410N have a significantly increased catalytic activity of 1018% (p. 84 Table 14). Madison et al. also disclose the amino acid replacement at R338 is selected from among at least R338L (at least paragraphs 0010, 0011, 0014)
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to arrive at the claimed FIX variant comprising a light chain and a
heavy chain, and wherein E410 (i.e. E265 of instant SEQ ID NO: 3) is substituted with Lys and R338 (i.e. R193 of instant SEQ ID NO: 3) is substituted with Leu (instant claims 1-2). The motivation to do so is given by Madison et al., which disclose and identify amino acid replacements in modified FIX polypeptides improve the therapeutic properties of FIX proteins, including increased activity and increased half-life, where the double amino acid substitution at position E410 and R338 has significantly increased catalytic activity compared to wild-type FIXa. One of ordinary skill would have a reasonable expectation of success because Madison et al. disclose and identify specific amino acid replacements within FIX polypeptides that contribute to improved properties.
Regarding instant claim 3, Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419); Madison et al. disclose modifications to reduce immunogenicity, including the amino acid replacements V223Y (at least paragraph 0419, p. 48 paragraph 0419), F342H (p. 49 paragraph 0419). Therefore, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein V223 (i.e. V78 of instant SEQ ID NO: 3) is substituted with Tyr.
Regarding instant claim 11, Madison et al. also disclose including the activated form of the modified FIX polypeptides (at least paragraph 0122).
Regarding instant claim 10, Madison et al. disclose compositions comprising said modified FIX polypeptides and at least one pharmaceutically acceptable carrier (at least paragraph 0035).
Regarding instant claims 12-14, 23, Madison et al. disclose methods of treatment of a hemostasis related disorder comprising administering said modified FIX polypeptides (at least paragraphs 0541-0551), where the disorder is hemophilia B (at least paragraphs 0552-0561), to a subject. Additionally, regarding instant claim 23, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein E410 (i.e. E265 of instant SEQ ID NO: 3) is substituted with Lys and R338 (i.e. R193 of instant SEQ ID NO: 3) is substituted with Leu, as noted above for instant claims 1-2.
Regarding instant claims 15, 17-19, Madison et al. disclose nucleic acid molecules encoding said modified FIX polypeptides, expression vectors comprising the nucleic acid molecules, host cells comprising the nucleic acid molecules, and methods of expressing the modified FIX polypeptides (at least paragraphs 0436-0467). Regarding instant claim 20, Madison et al. disclose methods of treatment comprising administering an expression vector comprising the nucleic acid molecules encoding said modified FIX polypeptides (at least paragraphs 0528-0540), to a subject, the vector being an adeno-associated virus vector (at least paragraph 0532). Additionally, regarding instant claim 27, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein E410 (i.e. E265 of instant SEQ ID NO: 3) is substituted with Lys and R338 (i.e. R193 of instant SEQ ID NO: 3) is substituted with Leu, as noted above for instant claims 1-2.
Regarding instant claim 22, as noted above, Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419); Madison et al. disclose modifications to reduce immunogenicity, including the amino acid replacements V223Y (at least paragraph 0419, p. 48 paragraph 0419), F342H (p. 49 paragraph 0419). Therefore, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein F342 (i.e. F197 of instant SEQ ID NO: 3) is substituted with His.
Regarding instant claims 25, 29, as noted above, Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419); Madison et al. disclose modifications to reduce immunogenicity, including the amino acid replacements V223Y (at least paragraph 0419, p. 48 paragraph 0419), F342H (p. 49 paragraph 0419). Therefore, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein V223 (i.e. V78 of instant SEQ ID NO: 3) is substituted with Tyr. Regarding instant claims 26, 30, as noted above, Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419); Madison et al. disclose modifications to reduce immunogenicity, including the amino acid replacements V223Y (at least paragraph 0419, p. 48 paragraph 0419), F342H (p. 49 paragraph 0419). Therefore, it would have been obvious to arrive at the claimed FIX variant comprising a light chain and a heavy chain, and wherein F342 (i.e. F197 of instant SEQ ID NO: 3) is substituted with His.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Instant claim 1 is drawn to a Factor IX variant, wherein the Factor IX variant comprises a light chain and heavy chain, wherein the light chain comprises SEQ ID NO: 2, wherein the heavy chain comprises SEQ ID NO: 3, where amino acid residues in SEQ ID NO: 3 are substituted as recited in claims 1(a), 1(b), or 1(c). Specifically, the amino acid substitutions in the Factor variant of instant claim 1 are (a) E265K/R193L, which corresponds to E410K/R338L in the numbering used in Madison et al.; (b) V78Y, which corresponds to V223Y in Madison et al.; or (c) F197H, which corresponds to F342H in Madison et al.
For the purposes of the arguments made herein, the instant amino acid positions and/or substitutions will be referred to according to the numbering used in Madison et al.
Regarding Applicants’ remarks on the E410K/R338L substitution, Applicants assert that in Table 14 of Madison et al., the Factor IX variant is a double substitution R338E/E410N and not the R338L/E410K recited in the instant claims. Applicants assert that notably, Table 15 of Madison et al. teach that the Factor IX variant with the R338E/410N has an activity of 950% of wildtype – not the 1018% noted by the examiner in Table 14. Applicants then assert that all of the other substitutions at position 410 performed worse than E410N. Applicants assert that Table 15 indicates that E410Q, E410S, E410A, and E410D had activity that was 261%, 239%, 241%, and 130% of wild-type, respectively. Applicants assert that based on this data, why would the skilled artisan replace the asparagine at position 410 of Madison et al. with another amino acid?
Applicants’ remarks are not persuasive. It is known that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123.
In this instance, and also noted by Applicants, all the substitutions at positions E410 and R338, combined in Madison et al., are Factor IX variants having a much greater catalytic activity than the wildtype Factor IX, i.e. 1018% in Table 14 and 950% in Table 15. Even the single E410 substitutions noted by Applicants in Table 15 have greater catalytic activity than the wildtype Factor IX. Therefore, it is not clear how Madison et al. would teach away from amino acid substitutions at the amino acid positions E410 and R338.
As previously noted, one of ordinary skill would not need to consider all the combinations asserted by Applicants to arrive at the claimed FIX variant because Madison et al. expressly disclose which variants at which positions display markedly increased catalytic activity compared to wild-type FIXa, thereby providing guidance to arrive at the same positions recited.
While Madison et al. do disclose other amino acid substitutions along with position E410, it is expressly disclosed in Madison et al. that some of the variants displayed markedly increased catalytic activity compared to wild-type FIXa, including single amino acid substitutions FIXa-R338E, FIXa-R338A, FIXa-T343R, FIXa-E410N, and combinations thereof, such as at least R338E with E410N (paragraph 0602). It is disclosed that single amino acid substitutions at position E410 have an increased catalytic activity including 297% for E410N (p. 83 Table 14), 269% E410Q, 246% E410S, 248% E410A, 134% E410D (p. 85 Table 14). It is disclosed that single amino acid substitutions at positions R338 also have markedly increased catalytic activity, 361% R338A and 408% R338E (p. 84 Table 14), and further that the double amino acid substitutions at R338E/E410N have a significantly increased catalytic activity of 1018% (p. 84 Table 14).
Therefore, Madison et al. have clearly identified that amino acid substitutions at positions E410 and R338 of a FIX variant has significantly increased catalytic activity compared to wild-type FIXa; and, it would have been obvious to arrive at a FIX variant where the amino acid residues at positions E410 and R338 are substituted with a different amino acid residue, in view of Madison et al.
As noted above, Madison et al. disclose the amino acid replacement at R338 is selected
from among at least R338L (at least paragraphs 0010, 0011, 0014). As noted above, Madison et
al. disclose the amino acid replacement at E410 can also be selected from among E410K, E410R,
E410Y, E410H (at least paragraph 0008, 0419). Therefore, it would have been obvious to arrive
at the recited amino acid substitutions R338L and E410K and E410K/R338L, where one of
ordinary skill would have reasonable expectation that the combination of E410K/R338L in a FIX
variant also has significantly increased catalytic activity because Madison et al. has already
disclosed that a FIX variant having substitutions at just positions E410 and R338 has
significantly increased catalytic activity of 1018% (paragraph 0602, p. 84 Table 14).
Therefore, Applicants’ remarks that Madison et al. is completely void of any guidance for
the skilled artisan to combine a substitution at the Glu at position 410 with Lys and a substitution of the Arg at position 338 with Leu, are not persuasive.
In this instance, arriving at alternative amino acid substitutions at the E410 position, including the recited E410K substitution and R338L substitution, in the FIXa-R338E/E410N
variant of Madison et al. would have been obvious because Madison et al. has already disclosed
these same amino acid substitutions for position E410 and further exemplify that a FIX variant
having double amino acid substitutions at positions R338 and E410 has a significantly increased
catalytic activity of 1018% (p. 84 Table 14).
Applicants assert that inasmuch as the assay of Madison et al. and the assay of the instant application both measure the activity of the FIX variant by determining the variant’s ability to form the Xase complex and to cleave and activate FX, Applicants submit that these assays are comparable. Applicants assert that the examiner has failed to provide any scientific basis to the contrary.
Applicants’ remarks are not persuasive. As previously noted, it is expressly disclosed and acknowledged in the prior art that an “activity” of a FIX polypeptide refers to any activity exhibited by a FIX polypeptide; such activities can be tested in vitro and/or in vivo and include, but are not limited to, coagulation or coagulant activities, pro-coagulant activity, proteolytic or catalytic activity such as to effect FX activation (Madison et al. paragraph 0138).
Madison et al. disclose “coagulation activity" or "coagulant activity" or "pro-coagulant activity" refers to the ability of a polypeptide to effect coagulation. Assays to assess coagulant activity are known to those of skill in the art, and include prothrombin time (PT) assay or the activated partial thromboplastin time (aPTT) assay (at least paragraph 0141).
Madison et al. disclose "catalytic activity" or "proteolytic activity" with reference to FIX refers to the ability of a FIX protein to catalyze the proteolytic cleavage of a substrate, and are used interchangeably. Assays to assess such activities are known in the art (at least paragraph 0142).
Therefore, it is acknowledged that the different activities of FIX, including “coagulation” (or “clotting”) activity and “catalytic” activity are measured on different assays and assessed differently.
The instant specification at examples 1 and 2 disclose assessing the FIX variants by a FIX specific clotting assay and an aPTT-based clotting assay. As noted above, Madison et al. disclose clotting assays, including aPTT assays are for assessing coagulating activity (at least paragraph 0141). Therefore, the assays used in the instant specification are measuring coagulant activity or clotting activity of the FIX variants, which is a different activity than what is being measured in Table 14 of Madison et al. Table 14 of Madison et al. shows the markedly increased catalytic activity of the FIX variants compared to wild-type FIXa, which are measured with assays using synthetic substrates (at least paragraphs 0142, 0595). The assays in examples 1 and 2 of the instant specification for measuring coagulant activity are materially and functionally different than the assays for measuring the catalytic activity of the FIX variants in Table 14 of Madison et al.
Regarding Applicants’ remarks that the data from the assays in Madison et al. and the instant application are both normalized against wild-type FIX activity, the remarks are not persuasive. The activity presented in Table 14 of Madison et al. is FIX catalytic activity and is assessed by an assay that is completely different than the assays in examples 1-2 of the instant application, which are assays assessing FIX coagulant activity.
Therefore, Applicants’ remarks that the assays measure comparable activities and functionalities and are properly comparable for purposes of showing unexpectedly superior results are not found persuasive.
Applicants’ remarks regarding the difference in fold increase between the activity tested in Madison et al. and the instant specification are not persuasive because different activities or functionalities are being tested and are not properly compared.
Applicants assert that the present application has demonstrated that the Factor IX variant comprising E410K and R338L possesses unexpectedly superior properties. Applicants assert that Table 1 of the present application provides the activity level (specific activity) of the tested Factor IX variants compared to wild-type Factor IX. Applicants assert that significantly, the combination of the E410K and R338L substitutions resulted in a Factor IX activity that was surprisingly 17-fold greater than wild-type. Applicants assert that Madison et al. fail to synthesize and characterize Factor IX variants comprising an E410K. Applicants assert that rather, Madison et al. tested the substitutions E410N, E410Q, E410S, E410A, and E410D. Applicants assert that as seen in Table 14 of Madison et al., the catalytic activity of these Factor IX variants of Madison et al. only show an activity which is 134% to 297% of wild-type (i.e., less than a threefold increase).
Applicants’ remarks regarding unexpectedly superior activity are not persuasive because
this is not a proper comparison. Madison et al. is testing the catalytic activity of the substitutions, including the E410 substitutions, in Table 14. In Table 1 of the instant specification, example 1 discloses that the specific activity being tested is clotting activity
(paragraph 0074). Therefore, Applicants’ remarks regarding the difference in fold increase
between the activity tested in Madison et al. and the instant specification are not persuasive
because different activities or functionalities are being tested and are not properly compared.
Further, Applicants’ assertion of unexpectedly superior activity (table 1 of specification) would flow naturally from following the suggestion of the prior art. See also MPEP 2145. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
As noted above, Madison et al. has already disclosed that a FIX variant having
substitutions at just positions E410 and R338 (R338E/E410N) has significantly increased
catalytic activity (1018%) compared to wild-type FIX (paragraph 0602, p. 84 Table 14). Madison et al. further disclose the amino acid replacement at R338 is selected from among at least R338L (at least paragraphs 0010, 0011, 0014) and the amino acid replacement at E410 can also be selected from among E410K (at least paragraph 0008, 0419). Therefore, it would have been obvious to arrive at the recited amino acid substitutions R338L and E410K and E410K/R338L, where one of ordinary skill would have reasonable expectation that the combination of E410K/R338L in a FIX variant also has significantly increased catalytic activity because Madison et al. has already disclosed that a FIX variant having substitutions at just positions E410 and R338 has significantly increased catalytic activity of 1018% (paragraph 0602, p. 84 Table 14).
Therefore, Madison et al. provide guidance to arrive at a FIX variant where the amino acid residues at positions E410 and R338 are substituted with Lys (K) and Leu (L), respectively, which are the same positions and substitutions recited in instant claim 1.
Therefore, Applicants’ remarks on the E410K/R338L FIX variant are not found persuasive.
Regarding the V223Y substitution, Applicants assert that Madison et al. clearly fail to teach or suggest these Factor IX variants. Applicants assert that Madison et al. state that their Factor IX variants may comprise a “further modification” and then provides a list of thousands of different amino acid substitutions. Applicants assert that significantly, it is clear that Madison et al. only contemplate the use of these amino acid substitutions in combination with another amino acid substitution.
Applicants’ remarks are not persuasive.
It is known that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123.
In this instance, Madison et al. expressly disclose that exemplary amino acid modifications that can contribute to reduced immunogenicity of a FIX polypeptide include any one or more amino acid modifications (at least paragraph 0419), where the amino acid substitution V223Y is expressly disclosed and identified (paragraph 0419). Therefore, Madison et al. reasonably contemplate a FIX polypeptide having only one substitution, where the substitution is V223Y.
While paragraph 0418 of Madison et al. disclose that the modifications are made further to a modified FIX polypeptide, it is noted that paragraph 0419 does not disclose that the FIX polypeptide is a modified FIX polypeptide. Therefore, Madison et al. fairly disclose a FIX polypeptide having one substitution, where the substitution is V223Y.
Further, even if Madison et al. disclose that a V223Y substitution is combined with another amino acid substitution in a FIX variant as asserted by Applicants, it would still render the claimed V223Y FIX variant obvious.
The instant claim 1 recites wherein the heavy chain comprises SEQ ID NO: 3, wherein the Val at position 78 of SEQ ID NO: 3 is substituted with Tyr (i.e. V223Y).
It is known that the transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. MPEP 2111.03.
The recitation of comprising in the instant claim means that other substitutions can be present in the FIX variant, in addition to the recited V223Y substitution. The instant claim does not preclude the inclusion of other substitutions so long as the V223Y substitution is present.
Therefore, even if Madison et al. disclose the V223Y substitution can be combined with another substitution in the FIX variant as asserted by Applicants, Madison et al. still disclose a FIX variant where the amino acid residue at position V223 is substituted with Tyr (Y), which is the same position and substituted recited in instant claim 1(b).
Regarding Applicants’ remarks that the present application has demonstrated that the V223Y substitution yields a Factor IX with superior activity, the remarks are not persuasive because Applicants’ assertion of superior activity (table 1 of specification) would flow naturally from following the suggestion of the prior art. See also MPEP 2145. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In this instance, Madison et al. expressly disclose the same substitution recited (V223Y) in a FIX variant contributes to a FIX variant having reduced immunogenicity. Therefore, Madison et al. provide guidance to arrive at a FIX variant where the amino acid residue at position V223 is substituted with Tyr, which is the same position recited in instant claim 1.
Regarding Applicants’ remarks that Madison et al. do not teach or suggest an increased activity in a FIX variant comprising the V223Y substitution, the remarks are not persuasive because there is no requirement under 103 that a reference must supply actual data or exemplify all embodiments taught.
Regarding Applicants’ remarks on instant claims 25, 29, Applicants’ remarks are not persuasive for the reasons noted above and in the 103 rejection.
Regarding the F342H substitution, Applicants assert that Madison et al. clearly fail to teach or suggest these Factor IX variants. Applicants assert that Madison et al. state that their Factor IX variants may comprise a “further modification” and then provides a list of thousands of different amino acid substitutions. Applicants assert that significantly, it is clear that Madison et al. only contemplate the use of these amino acid substitutions in combination with another amino acid substitution.
Applicants’ remarks are not persuasive. As similarly noted above for the V223Y substitution, it is known that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In this instance, Madison et al. expressly disclose that exemplary amino acid modifications that can contribute to reduced immunogenicity of a FIX polypeptide include any one or more amino acid modifications (at least paragraph 0419), where the amino acid substitution F342H is expressly disclosed and identified (paragraph 0419). Therefore, Madison et al. reasonably contemplate a FIX polypeptide having only one substitution, where the substitution is F342H.
While paragraph 0418 of Madison et al. disclose that the modifications are made further to a modified FIX polypeptide, it is noted that paragraph 0419 does not disclose that the FIX polypeptide is a modified FIX polypeptide. Therefore, Madison et al. fairly disclose a FIX polypeptide having one substitution, where the substitution is F342H.
Further, even if Madison et al. disclose that a F342H substitution is combined with another amino acid substitution in a FIX variant as asserted by Applicants, it would still render the claimed F342H FIX variant obvious.
The instant claim 1 recites wherein the heavy chain comprises SEQ ID NO: 3, wherein the Phe at position 197 of SEQ ID NO: 3 is substituted with His (i.e. F342H).
It is known that the transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. MPEP 2111.03.
The recitation of comprising in the instant claim means that other substitutions can be present in the FIX variant, in addition to the recited F342H substitution. The instant claim does not preclude the inclusion of other substitutions so long as the F342H substitution is present.
Therefore, even if Madison et al. disclose the F342H substitution can be combined with another substitution in the FIX variant as asserted by Applicants, Madison et al. still disclose a FIX variant where the amino acid residue at position F342 is substituted with His (H), which is the same position and substituted recited in instant claim 1(c).
Applicants’ remarks regarding unexpectedly superior activity are not persuasive because
this is not a proper comparison. Madison et al. is testing the catalytic activity of the substitutions, including the F342I substitution, in Table 14. In Table 1 of the instant specification, example 1 discloses that the specific activity being tested is clotting activity
(paragraph 0074). Therefore, Applicants’ remarks regarding the difference in fold increase
between the activity tested in Madison et al. and the instant specification are not persuasive
because different activities or functionalities are being tested and are not properly compared.
Further, Applicants’ assertion of unexpectedly superior activity (table 1 of specification) would flow naturally from following the suggestion of the prior art. See also MPEP 2145. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Madison et al. has disclosed that a FIX variant having a substitution at just position F342 has increased catalytic activity (121%) compared to wild-type FIX (paragraph 0602, p. 85 Table 14). Madison et al. further disclose the amino acid replacement at F342 is selected from among at least F342H (at least paragraph 0419). Therefore, Madison et al. provide guidance to arrive at a FIX variant where the amino acid residue at position 342 is substituted with His, which is the same position recited in instant claim 1.
For at least these reasons, the 103 rejection is maintained.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached on M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marsha Tsay/Primary Examiner, Art Unit 1656